1. J. Mehilli, A. Kastrati, K. Huber, S. Schulz, J. Pache, C.Markwardt, S. Kufner, F. Dotzer, K. Schlotterbeck, J. Dirschinger, A. Schömig Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment BRAVE-3 Trial Bavarian Reperfusion AlternatiVes Evaluation-3 Trial ClinicalTrials.gov Identifier: NCT00133250

2. Financial Disclosure No financial relationship to disclose

3. Background  Glycoprotein IIb/IIIa inhibitors (GPI) may improve the results of primary PCI in acute STEMI  Pretreatment with a 300mg loading dose of clopidogrel improved the outcome of patients undergoing primary PCI in the setting of the CLARITY trial  A higher, 600mg loading dose of clopidogrel further enhances and accelerates platelet inhibition

4. Objective..to assess whether abciximab further reduces the infarct size in patients with acute ST-elevation myocardial infarction undergoing primary PCI after pre-treatment with 600 mg clopidogrel

5. Inclusion Criteria  Patients with acute ST-elevation myocardial infarction presenting within 24 hours from the onset of symptoms  Written, informed consent chest pain lasting more than 20 min ≥0.1 mV of ST-segment elevation in ≥2 limb leads or ≥0.2 mV in ≥2 contiguous precordial leads or new left bundle branch block on surface ECG

6. Exclusion Criteria  Age > 80 or < 18 years  Malignancies with a life expectancy <1 year  Cardiogenic shock or prolonged cardiopulmonary resuscitation  Increased risk of bleeding Previous stroke within the last 3 months Active bleeding or bleeding diatheses Recent trauma or major surgery within the last 30 days Suspected aortic dissection Recent use of GPI within 14 days Oral anticoagulation therapy with coumarin derivatives Severe uncontrolled hypertension (>180mmHg, unresponsive to therapy)  Relevant hematologic deviations (hemoglobin < 100g/L or hct < 34%, platelet count < 100 x 10 9 /L)  Coronary intervention within the last 30 days  Known allergy to study medication, Pregnancy, Prior inclusion in the study

7. Endpoints  Final infarct size (% of the left ventricle) SPECT study (5-7 days after randomization) Primary endpoint: Myocardial perfusion % 100% 0% 50% Secondary endpoints:  Death  Myocardial reinfarction  Urgent revascularization  Stroke  Major and minor bleeding (TIMI criteria)  Profound thrombocytopenia

8. Sample Size Calculation Assumptions:  Infarct size of the LV in placebo group: 16.9% ± 13.9%  Reduction of infarct size with abciximab by 20%   -level: 0.05 (two-sided);  -error: 0.10 Sample size:  353 patients per group with SPECT study  to accommodate for possible missing SPECT studies: 400 patients per group planned

9. BRAVE-3 Study Sides & Investigators  Deutsches Herzzentrum, Munich, Germany PI: M. Seyfarth  Klinikum rechts der Isar, Munich, Germany PI: J. Dirschinger  Klinikum Traunstein, Traunstein, Germany PI: K. Schlotterbeck  Wilhelminenspital Vienna, Vienna, Austria PI: K. Huber  Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany PI: F. Dotzer Study Chair: A. Schömig Study Principal Investigator: A. Kastrati Data Co-ordinator: J. Mehilli

10. Clopidogrel 600 mg oral Aspirin 500 mg i.v. or oral Unfractionated Heparin 5000 IU Study Therapy (randomized, double-blind) Placebo n=399 Additional UFH bolus of 70U/kg Placebo infusion for 12h Abciximab n=401 Bolus: 0.25 mg/kg Infusion: 0.125 μg/kg/min/12h Aspirin 200mg/day indefinitely Clopidogrel 2 x 75mg/day for 3 days Clopidogrel 75mg/day for at least 4 weeks

11. Baseline Characteristics Mean±SD Age, yrs Women, % Hypercholesterolemia, % Body mass index, kg/m 2 Arterial hypertension, % Diabetes mellitus, % Current smoker, % Previous MI, % Previous CABG, % Abciximab (n=401) 62.4±11.7 24 42 27.1±3.8 70 19 42 10 4 Placebo (n=399) 61.8±12.2 27 44 27.0±4.1 71 16 41 11 2

12. Infarct Characteristics Abciximab (n=401) Placebo (n=399) Infarct localization, % anterior 4244 Mean±SD or % inferior 43 lateral 1513 Killip Class, % I7677 II18 III43 IV22 Arterial blood pressure, mmHg systolic 138±23139±22 diastolic80±1479±13 Heart rate, beats/min 73±1773±16

13. Time Intervals Admission to study drug Admission to PCI Symptom to admission Clopidogrel loading to PCI Abciximab (n=401) 25 [15;43] 78 [59;109] 210 [110;420] 73 [54;104] Placebo (n=399) 20 [14;40] 80 [58;110 ] 216 [110;467] 75 [53;105] Median [25 th, 75 th percentiles] in minutes

14. Angiographic Characteristics Infarct related coronary artery, % LAD LCx LMA Bypass graft RCA Mean±SD LV- ejection fraction, % Multivessel disease, % 43 16 0 2 39 47.7±11.5 Abciximab (n=401) 65 45 15 1 1 38 48.0±10.6 Placebo (n=399) 61

15. 100 60 20 % 100 60 20 % Infarct-Related Artery TIMI Flow Rates AbciximabPlaceboAbciximabPlacebo Prior to PCI After PCI TIMI 3TIMI 2TIMI 1TIMI 0

16. Collateral Distribution 100 60 20 % AbciximabPlacebo Rentrop class 3 Rentrop class 2 Rentrop class 1 No collaterals IRA TIMI Flow rate <2

17. QCA Measurements DS after PCI, % Balloon diameter, mm Vessel size, mm Maximal balloon pressure, atm MLD prior PCI, mm DS prior PCI, % Balloon-to-vessel ratio Mean±SD MLD after PCI, mm 13.8±16.4 3.26±0.53 2.93±0.54 13.5±2.6 0.46±0.56 84.1±19.4 1.11±0.09 2.62±0.67 Abciximab (n=401) 13.6±15.2 3.26±0.52 2.91±0.56 13.4±2.5 0.44±0.57 84.3±20.6 1.12±0.12 2.63±0.65 Placebo (n=399)

18. Reperfusion Strategy 100 60 20 % AbciximabPlacebo Drug-eluting stents Bare metal stents PTCA Medical treatment

19. Primary Endpoint % LV AbciximabPlacebo Final infarct size Median [25th; 75th percentile] Final infarct size Mean % LV P =.47 AbciximabPlacebo P =.76 10 9 0 20 30 40

20. Primary Endpoint - Subgroup analysis - Abciximab better -8-6-4-202468 Age Sex Diabetes Infarct localization Interval pain onset to admission Interval study drug to PCI Interval clopidogrel to PCI > 74.5 min Placebo better Difference in Final Infarct Size (%) ≤ 74.5 min > 47 min ≤ 47 min > 210 min ≤ 210 min non-anterior anterior All ≤ 62.5 yrs > 62.5 yrs female male yes no

21. 30-Day Mortality Days after randomization Cumulative Incidence 0 2 4 051015202530 Abciximab Placebo P =.53 6 %

22. Clinical Adverse Events - 30 days - AbciximabPlacebo % P =.48P =.46P =.39

23. Clinical Adverse Events - 30 days - 1.8 3.7 1.5 1.8 0 0 2 4 6 TIMI majorTIMI minor<20,000/µl Bleeding Thrombocytopenia P =.03P =.09P =.99 % AbciximabPlacebo

24. Conclusion In patients with acute STEMI undergoing primary PCI after pre-treatment with a 600mg loading dose of clopidogrel, the additional use of abciximab is not associated with further reduction in infarct size